Renbarger Jamie L, McCammack Kevin C, Rouse Caroline E, Hall Stephen D
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Pediatr Blood Cancer. 2008 Apr;50(4):769-71. doi: 10.1002/pbc.21435.
This report examines the association between race and vincristine-associated neurotoxicity in pediatric patients with precursor B cell acute lymphoblastic leukemia (preB ALL). Given that in vitro vincristine is metabolized more efficiently by cytochrome P450 (CYP) 3A5 than by CYP3A4 and that 70% African-Americans (vs. 20% of Caucasians) express CYP3A5, one may hypothesize that African-Americans metabolize vincristine more efficiently resulting in lower vincristine exposure and associated-toxicity.
A retrospective analysis of vincristine-related side effects in pediatric patients treated for preB ALL was performed. Data were compared between Caucasians (n = 92) and African-Americans (n = 21) to examine the relationship between race and vincristine-associated neurotoxicity thus using race as a surrogate for CYP3A5 genotype. Race, age, gender, disease subtype, highest grade of vincristine-associated neurotoxicity (per NIH Common Terminology Criteria for Adverse Events version 3.0), number of omitted and reduced vincristine doses, cumulative vincristine dose, and disease outcome were captured.
34.8% of Caucasians experienced symptoms consistent with vincristine-related neurotoxicity compared to 4.8% of African-Americans (P = 0.007). The average grade of neurotoxicity for Caucasians was 2.72 versus grade 1 neurotoxicity in the African-American (P < 0.0001). Four percent of total doses administered to Caucasian patients were reduced due to vincristine-related neurotoxicity compared to 0.1% given to African-Americans (P < 0.0001). 1.2% of all protocol-indicated doses for Caucasians were held due to severe vincristine-associated toxicity compared to 0.1% of doses for African-Americans (P < 0.01).
The data support the hypothesis pharmacogenetic polymorphisms in CYP3A5 expression contribute to variability in vincristine metabolism and neurotoxicity.
本报告研究了前体B细胞急性淋巴细胞白血病（preB ALL）患儿中种族与长春新碱相关神经毒性之间的关联。鉴于体外实验中，细胞色素P450（CYP）3A5对长春新碱的代谢效率高于CYP3A4，且70%的非裔美国人（相比20%的白种人）表达CYP3A5，有人可能会推测非裔美国人对长春新碱的代谢效率更高，从而导致长春新碱暴露量降低及相关毒性降低。
对接受preB ALL治疗的儿科患者中与长春新碱相关的副作用进行回顾性分析。比较了白种人（n = 92）和非裔美国人（n = 21）的数据，以研究种族与长春新碱相关神经毒性之间的关系，从而将种族作为CYP3A5基因型的替代指标。记录了种族、年龄、性别、疾病亚型、长春新碱相关神经毒性的最高等级（根据美国国立卫生研究院不良事件通用术语标准第3.0版）、遗漏和减少的长春新碱剂量数量、长春新碱累积剂量以及疾病转归。
34.8%的白种人出现了与长春新碱相关神经毒性一致的症状，而非裔美国人中这一比例为4.8%（P = 0.007）。白种人的神经毒性平均等级为2.72，而非裔美国人为1级神经毒性（P < 0.0001）。由于长春新碱相关神经毒性，白种人患者接受的总剂量中有4%被减少，而非裔美国人中这一比例为0.1%（P < 0.0001）。由于严重的长春新碱相关毒性，白种人所有方案规定剂量中有1.2%被停用，而非裔美国人中这一比例为0.1%（P < 0.01）。
数据支持这样的假设，即CYP3A5表达中的药物遗传多态性导致了长春新碱代谢和神经毒性的变异性。
